ABSTRACT. Problem. There are distinct sex-based differences that affect the natural history of HIV infection and HIV- specific immune responses. These differences are partially driven by sex hormones (estrogens in particular) and might influence the size, distribution and transcriptional activity of the HIV reservoirs. Globally, women account for over half of all people living with HIV but represent only 11% of participants in HIV cure research resulting in a significant knowledge gap between the biology of HIV in men and women. Even less is known about how this effect changes when women are entering menopause and hormonal levels starts to decline. What we know now. ? Women have lower levels of HIV DNA in peripheral blood mononuclear cells (PBMCs) than men. ? Various in vitro studies reported sex-based differences on HIV infection and replication in target cells. ? Women have different HIV-specific immune responses than men. ? These differences are partially driven by estradiol that inhibits HIV replication in PBMCs through estrogen receptor dependent mechanisms. A recent ex vivo study (by Jon Karn et al) provided strong evidence that estrogen inhibits HIV transcriptional activity in a sex-specific manner. Proposed Solution. We will request longitudinal stored samples from 30 HIV-infected women aged 40-55 at enrollment (not taking hormonal therapy) and 30 men (similar age) on antiretroviral therapy (ART) with suppressed HIV RNA for >48 weeks. This age range was selected to maximize variability in hormonal levels (across study participants and longitudinally) and because younger women are more likely to take hormonal therapy. Our goal. We will characterize extensively the HIV reservoir and generate immunological data at each time- point. We will use these data to determine the effect of sex hormones and receptor expression (in particular estradiol) on the HIV reservoir size and transcriptional activity over 3+ years of follow-up while on ART. We will compare these data with a similar group of men. How will we advance the field. To date, the majority of HIV cure research has used male participants and therefore a significant knowledge gap exists between men and women. We do not know if the same immune- modulatory interventions will be effective in promoting HIV RNA transcription in men and women and how declining sex hormones will impact their efficacy. In particular, agents that are designed for ?kick and kill? strategies may be especially impacted by estradiol-mediated mechanisms. A better understanding of these differences will assist in the design of future cure approaches that can be applied across sexes.